Abstract LB-128: Targeted RNAi screening of an EGFR network reveals molecular determinants of tumor cell sensitivity to antibody-dependent cellular cytotoxicity (ADCC)

Abstract

Abstract Monoclonal antibodies can modulate signal transduction and survival of tumor cells, and can induce antibody-dependent cellular cytotoxicity (ADCC) through immune effectors, such as natural killer (NK) cells. Although clinical evidence suggests a role for ADCC in effective antibody therapy, molecular determinants of ADCC responsiveness—in oncogenic signaling networks, for example—have not been identified. Using a novel high-throughput screening platform, siRNAs targeting 60 genes of an EGFR network were reverse transfected into A431 cells, and cetuximab and an NK-like cell line (NK92-CD16V) were used to induce ADCC. Primary and validation screens identified four genes whose knockdown enhanced ADCC: GRB7, PRKCE, RET and ABL1. Pharmacological inhibition of Abl kinase activity enhanced ADCC, recapitulating the effects of ABL1 gene knockdown. Additional studies revealed distinct mechanisms associated with enhanced ADCC, including increased EGFR surface expression and enhanced susceptibility to apoptosis. This screening strategy has revealed putative molecular determinants of tumor cell sensitivity to ADCC that may translate to increased monoclonal antibody efficacy in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-128. doi:1538-7445.AM2012-LB-128